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Interactive involvement of brain derived neurotrophic factor, nerve growth factor, and calcitonin gene related peptide in colonic hypersensitivity in the rat

¹ Pfizer Global Research and Development, Fresnes Laboratories, Fresnes cedex, France, and INSERM, U766, Faculté de Médecine, Clermont-Ferrand, France
² INSERM, U766, Faculté de Médecine, Clermont-Ferrand, France, Univ Clermont 1, Fac Médecine, Laboratoire de Pharmacologie, Clermont-Ferrand, France, and Univ Clermont 1, IUT de Biologie, Clermont-Ferrand, France
³ INSERM, U766, Faculté de Médecine, Clermont-Ferrand, France, Univ Clermont 1, Fac Médecine, Laboratoire de Pharmacologie, Clermont-Ferrand, France, and CHU Clermont-Ferrand, Service de Pharmacologie, Hôpital G Montpied, Clermont-Ferrand, France
⁴ Pfizer Global Research and Development, Fresnes Laboratories, Fresnes cedex, France

Correspondence to:
Correspondence to:
Dr A Gelot
Laboratoire de pharmacologie Médicale, Faculté de Médecine, 28 Place Henri Dunant, 63001 Clermont-Ferrand Cedex, France; Agathe.GELOT{at}u-clermont1.fr

ABSTRACT
Background and aims: Neutrophins are involved in somatic and visceral hypersensitivity. The action of nerve growth factor (NGF) on sensory neurones contributes to the development of referred colonic hypersensitivity induced by trinitrobenzene sulfonic acid (TNBS). Based on data on brain derived neurotrophic factor (BDNF) and calcitonin gene related peptide (CGRP) in pain, the aims of the present study were: (1) to investigate the involvement of BDNF and CGRP in this model of referred colonic hypersensitivity, (2) to test the effect of exogenous BDNF and CGRP on the colonic pain threshold, and (3) to investigate the relationship between BDNF, NGF, and CGRP by testing antineurotrophin antibodies or h-CGRP 8–37 (a CGRP antagonist) on bowel hypersensitivity induced by these peptides.

Methods: Colonic sensitivity was assessed using a colonic distension procedure.

Results: Anti-BDNF antibody and h-CGRP 8–37 reversed the induced decrease in colonic threshold (33.4 (2.1) and 40.3 (4.1) mm Hg, respectively, compared with a vehicle score of approximately 18 mm Hg; p<0.001). BDNF (1–100 ng/rat intraperitoneally) induced a significant dose dependent decrease in colonic reaction threshold in healthy rats. This effect was reversed by an anti-BDNF antibody and an anti-NGF antibody (33.4 (0.6) v 18.7 (0.7) mm Hg (p<0.001), anti-NGF v vehicle). NGF induced colonic hypersensitivity was reversed by h-CGRP 8–37 but not by the anti-BDNF antibody. Finally, antineurotrophin antibody could not reverse CGRP induced colonic hypersensitivity (at a dose of 1 µg/kg intraperitoneally).

Conclusion: Systemic BDNF, NGF, and CGRP can induce visceral hypersensitivity alone and interactively. This cascade might be involved in TNBS induced referred colonic hypersensitivity in which each of these peptides is involved.

Abbreviations: NGF, nerve growth factor; TNBS, trinitrobenzene sulfonic acid; BDNF, brain derived neurotrophic factor; CGRP, calcitonin gene related peptide; IBS, irritable bowel syndrome; SP, substance P; BSA, bovine serum albumin; h-CGRP 8–37, human calcitonin gene related and peptide fragment 8–37

Keywords: neurotrophins; neuropeptides; irritable bowel syndrome; colonic distension; rats

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